Is SRCAP p.Arg971His (c.2912G>A) pathogenic?

SRCAP p.Arg971His (c.2912G>A) is classified Uncertain significance in SRCAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1836); Ultra-rare (popmax 0.0245%, eas).

How common is SRCAP p.Arg971His (c.2912G>A) in the general population?

SRCAP p.Arg971His (c.2912G>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about SRCAP p.Arg971His (c.2912G>A)?

AlphaMissense predicts likely benign (score 0.1836) — an in-silico prediction, not a clinical call.

SRCAP p.Arg971His

c.2912G>A · rs200896833 · VCV2720309

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1836 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1836	likely benign
REVEL	0.271	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 4,608 bp · p 6.7e-06 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,886 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00136% 22/1,614,152 alleles · ultra-rare exomes 19/1,461,852 · genomes 3/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,081
Admixed American	0.00833%	12,001
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.00329%	30,361
European (non-Finnish)	0.000169%	590,009

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SRCAP
Protein: p.Arg971His
Coding: c.2912G>A
MANE Select: NM_006662
dbSNP: rs200896833
Type: single nucleotide variant
Location: chr16:30720256 (GRCh38)
Gene constraint: LOEUF 0.223 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 971: an α-helix; a UniProt-annotated variant site (in dehmba)

Full SRCAP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SRCAP p.Arg971Cys Uncertain significance ★ same residue
SRCAP p.Arg971= Likely benign ★ same residue
SRCAP p.Arg2329Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2435Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2444Ter Pathogenic ★★ same type
SRCAP p.Arg2718Ter Pathogenic/Likely pathogenic ★★ same type
SRCAP p.Arg2748Ter Pathogenic ★★ same type
SRCAP p.Gln2407Ter Pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/srcap-p-arg971his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown